1. Field of the Invention
The invention relates to the field of separation of molecules using selective adsorbents.
2. DESCRIPTION OF THE ART
Since its discovery by Tswett nearly a century ago, the technique of adsorption chromatography has evolved into a tool of fundamental importance to the biological and chemical sciences. Early chromatographers employed readily available adsorbents such as calcium carbonate, sugar, starch, paper, wool, silk, alumina and silica to perform an impressive variety of separations. Today, researchers with a problem separation are faced with a variety of adsorbents from which to choose. Furthermore, additional adsorbents can readily be prepared using combinatorial chemistry approaches. As a general rule, the more selective adsorbents allow for more economical chromatographic separations, with simple and inexpensive batch adsorption separations becoming possible with extremely selective adsorbents. A means of rapidly finding the most selective adsorbent for a given separation task is needed.
One area where the development of highly selective adsorbents is of great importance is the large scale separation of enantiomers using chiral stationary phases (CSPs). The current selection of commercial chiral stationary phases (CSPs) for large scale chromatographic separations is rather limited, and most have been developed as general purpose CSPs rather than the best CSP for a particular separation. While new CSPs can be designed, the development time is often too long to merit serious consideration by process engineers.
Within the past decade the technique of chromatographic enantioseparation has become the method of choice for analytical determinations of enantiopurity. Allenmark, Chromatographic Enantioseparation: Methods and Applications, Ellis Horwood, N.Y., 1991. The method is widely used, particularly in the pharmaceutical industry where most new chiral drugs are manufactured in enantiomerically pure form. In recent years the use of preparative chromatographic enantioseparation has become increasingly popular. While generally more expensive than manufacturing routes employing enantioselective synthesis or classical resolution, chiral HPLC offers a considerable advantage of speed. Consequently, many pharmaceutical companies use preparative chiral HPLC in the early stages of drug discovery to rapidly produce enantiomerically pure drug candidates for animal testing, metabolism and toxicology studies, etc. Once a drug candidate has been selected for larger scale development, alternative manufacturing methods are often used, although in a few cases chiral HPLC is used to produce enantiopure drugs on large scale.
Most commercial CSPs have been developed using trial and error methodology, and have been commercialized because they demonstrate some general ability to separate enantiomers. Of these many commercial CSPs, only a small fraction are available in bulk or can be produced in an economical fashion for large scale preparative chromatography. Francotte, E., J. Chromatogr., 666, 565-601, 1994. Furthermore, rather than a CSP which has a general ability to separate the enantiomers of a large number of racemates, the process engineer considering a potential manufacturing route for an enantiopure drug is interested in a CSP which can separate the enantiomers of one particular compound.
Practical large scale chromatographic enantioseparation requires highly enantioselective CSPs. For example, chromatographic resolution of the enantiomers of a racemate using a CSP with an enantioselectivity of 1.3 can be rather tedious. A comparable CSP having an enantioselectivity of 2 can sometimes afford 5-10 fold greater productivity.
The present invention relates to a process for screening candidate selective adsorbents for differential adsorption of two or more chemical components. In this process a solid phase consisting of the candidate adsorbent is allowed to contact a solution phase containing the component or components of interest. Interaction or equilibration of material in the solution phase with the stationary phase of the selective adsorbent results in a change of concentration of the analyte or analytes in both the stationary phase and solution phase. This change in concentration can be measured by a variety of techniques and gives an indication of the degree of adsorption of the analyte by the stationary phase. Thus, small amounts of candidate selective adsorbents are placed in an array of containers and a solution of the chemical compounds to be separated is added to each container. The components are allowed to interact or equilibrate with the selective adsorbent and the amount of each component in the solution phase or in the solid phase of the array of containers is measured. The adsorbent showing the greatest differential adsorption for the chemical components is identified as being potentially useful for large scale separations. The invention is particularly useful in identifying selective adsorbents for enantiomer separations.